M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer
Background The immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000979.full |
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| author | Vladimir Benes Ladislav Pecen Jelena Pistolic Lorenzo Galluzzi Iva Truxova Radek Špíšek Lenka Kasikova Michal Hensler Petr Skapa Jan Laco Ivan Praznovec Tomas Brtnicky Lukas Rob Catherine Sautes-Fridman Ales Ryska Jitka Fucikova Wolf Herve Fridman Vít Drochýtek Sarka Vosahlikova Karel Fiser Jana Rakova Tereza Lanickova Irena Moserova Martina Rehackova Ludek Sojka |
| author_facet | Vladimir Benes Ladislav Pecen Jelena Pistolic Lorenzo Galluzzi Iva Truxova Radek Špíšek Lenka Kasikova Michal Hensler Petr Skapa Jan Laco Ivan Praznovec Tomas Brtnicky Lukas Rob Catherine Sautes-Fridman Ales Ryska Jitka Fucikova Wolf Herve Fridman Vít Drochýtek Sarka Vosahlikova Karel Fiser Jana Rakova Tereza Lanickova Irena Moserova Martina Rehackova Ludek Sojka |
| author_sort | Vladimir Benes |
| collection | DOAJ |
| description | Background The immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases.Methods RNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples.Results 1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome.Conclusions Immunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs. |
| format | Article |
| id | doaj-art-0c6e706e32b54f77a1056e1dbd1de54b |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-0c6e706e32b54f77a1056e1dbd1de54b2024-11-10T04:45:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-000979M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancerVladimir Benes0Ladislav Pecen1Jelena Pistolic2Lorenzo Galluzzi3Iva Truxova4Radek Špíšek5Lenka Kasikova6Michal Hensler7Petr Skapa8Jan Laco9Ivan Praznovec10Tomas Brtnicky11Lukas Rob12Catherine Sautes-Fridman13Ales Ryska14Jitka Fucikova15Wolf Herve Fridman16Vít Drochýtek17Sarka Vosahlikova18Karel Fiser19Jana Rakova20Tereza Lanickova21Irena Moserova22Martina Rehackova23Ludek Sojka24Genomic Core Facility, European Molecular Biology Laboratory, Heidelberg, GermanyAff2 grid.476702.0Sotio Prague Czech RepublicGenomics Core Facility, European Molecular Biology Laboratory, Heidelberg, GermanyDepartment of Radiation Oncology, Weill Cornell Medical College, New York, NY, USASotio Biotech, Prague, Czech RepublicSotio Biotech, Prague, Czech RepublicAff1 0000 0004 1937 116Xgrid.4491.8Department of ImmunologyCharles University, 2nd Faculty of Medicine and University Hospital Motol Prague Czech RepublicAff2 grid.476702.0Sotio Prague Czech RepublicAff3 0000 0004 1937 116Xgrid.4491.8Department of Pathology and Molecular MedicineCharles University, 2nd Faculty of Medicine and University Hospital Motol Prague Czech RepublicAff4 0000 0004 1937 116Xgrid.4491.8The Fingerland Department of PathologyCharles University, Faculty of Medicine and University Hospital Hradec Kralove Hradec Kralove Czech RepublicAff5 0000 0004 1937 116Xgrid.4491.8Department of Gynecology and ObstetricsCharles University, Faculty of Medicine and University Hospital Hradec Kralove Hradec Kralove Czech RepublicAff7 0000 0004 1937 116Xgrid.4491.8Department of Gynecology and ObstetricsCharles University, 2nd Faculty of Medicine and University Hospital Motol Prague Czech RepublicThird Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech RepublicCentre de Recherche des Cordeliers, Inserm UMR S1138, Paris, FranceAff4 0000 0004 1937 116Xgrid.4491.8The Fingerland Department of PathologyCharles University, Faculty of Medicine and University Hospital Hradec Kralove Hradec Kralove Czech RepublicSotio Biotech, Prague, Czech Republic15 Department of Immunology, Inflammation and Cancer, Centre de Recherche des Cordeliers, Paris, France8Faculty Hospital Kralovske Vinohrady 3rd Medical Faculty, Charles University, Department of Obstetrics and Gynaecology, Prague, Czech Republic2 grid.476702.0Sotio Prague Czech Republic3 CLIP-Childhood Leukemia Investigation Prague, Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University Prague and University Hospital Motol, Prague, Czech Republic1 Sotio, Prague, Czech Republic1 Sotio, Prague, Czech Republic1 Sotio, Prague, Czech Republic7 Department of Gynecology and Obstetrics, Charles University, 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady, Prague, Czech Republic1 Sotio, Prague, Czech RepublicBackground The immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases.Methods RNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples.Results 1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome.Conclusions Immunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.https://jitc.bmj.com/content/8/2/e000979.full |
| spellingShingle | Vladimir Benes Ladislav Pecen Jelena Pistolic Lorenzo Galluzzi Iva Truxova Radek Špíšek Lenka Kasikova Michal Hensler Petr Skapa Jan Laco Ivan Praznovec Tomas Brtnicky Lukas Rob Catherine Sautes-Fridman Ales Ryska Jitka Fucikova Wolf Herve Fridman Vít Drochýtek Sarka Vosahlikova Karel Fiser Jana Rakova Tereza Lanickova Irena Moserova Martina Rehackova Ludek Sojka M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer Journal for ImmunoTherapy of Cancer |
| title | M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer |
| title_full | M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer |
| title_fullStr | M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer |
| title_full_unstemmed | M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer |
| title_short | M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer |
| title_sort | m2 like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer |
| url | https://jitc.bmj.com/content/8/2/e000979.full |
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